Abstract: Nicotine is considered to be the main addictive ingredient in tobacco. Therefore, the nicotine content of tobacco products may serve as a logical target in the development of effective tobacco-control policies. In their landmark article, Benowitz and Henningfield (B&H) proposed that the gradual reduction of the nicotine content of cigarettes to an amount below the threshold addictive dose could prevent the development of nicotine addiction among young smokers. B&H estimated that the threshold for nicotine addiction is approximately 0.17 mg of delivered nicotine per cigarette and predicted that nicotine doses below this threshold would neither be self-administered nor maintain nicotine addiction. Although proposed over 20 years ago, this estimated threshold for nicotine reinforcement remains to be systematically evaluated by carefully controlled human studies. Availability of such knowledge would provide a stronger scientific rationale for the potential risks and benefits of nicotine reduction approaches. This knowledge gap is partly due to the difficulty in assessing nicotine's reinforcing effects from currently available nicotine delivery systems in humans. While some nicotine delivery systems are not reliably reinforcing (e.g., nicotine gum or lozenge), others do not deliver accurate doses of nicotine or deliver many other chemicals in addition to nicotine (e.g., tobacco or e- cigarettes). To address these limitations, we have developed a novel intravenous (IV) nicotine self- administration (NSA) model for humans. IV nicotine closely mimics both the pharmacokinetics and behavioral effects of smoked nicotine, including reinforcement. The main goal of this project is to use IV NSA for estimating threshold reinforcing doses of nicotine and to generate dose-effect curves for low doses of nicotine in smokers. This application will also examine if the nicotine reinforcement threshold and dose-effect curve varies with gender and with the rate of nicotine metabolism. The study sample will be young adult male and female light and intermittent smokers (LITS), also known as `chippers', who show few or no signs of addiction. We propose a double-blind, placebo-controlled, crossover study that will enroll 36 male and 36 female LITS. Smokers will participate in five experimental sessions. In each session, they will first sample the assigned nicotine dose and the placebo (saline) dose followed by the opportunity to choose between nicotine and placebo administrations. The knowledge gained from this study will be useful in guiding strategies that lower nicotine content of tobacco products in order to reduce their addictive potential.